Cancer remains the second leading cause of death in the United States. Furthermore, cancer is noteworthy because it is primarily a genomic disease: most tumors arise and persist because of a constellation of genomic changes that dysregulate cell growth and survival. Germline variants may also confer increased disease risk or thwart cancer treatment options by altering drug metabolism. The transformative medical potential of cancer genomic information has been made clear by the growing number of targeted agents that show remarkable efficacy against tumors whose salient genetic events confer heightened therapeutic vulnerability. Some mutations also identify tumors for which a therapy will be futile o even harmful. Many cancer genes harbor potentially actionable mutations at variable frequencies across a wide range of tumor types. These observations provide a compelling rationale for a paradigm wherein all therapeutically relevant tumor genomic alterations might be presented to physicians in a manner that guides personalized treatment. At first blush, translating the cancer genome for clinical use seems straightforward (Figure 1): (i) characterize the genome by massively parallel sequencing; (ii) filter this data through a compendium of available drugs/ targets; and (iii) present an annotated list to expert clinicians. However, multipe challenges must be addressed in order to bring this audacious goal to fruition. The first is a technical challenge: quality sequencing data must be obtained from limiting amounts of archival tumor tissue. The second is an analytical challenge: we must identify somatic and germline genomic changes with high accuracy, and distinguish driver events from the much larger set of passenger alterations. The third is a clinical challenge: we must achieve actionable data interpretation and develop a framework whereby genomic information promotes evidence based clinical trials and disease management choices. Finally, there is a psychosocial and ethical challenge: we must rigorously evaluate patients' and oncologists' experiences of clinical sequencing, and develop principled approaches to confront the myriad uncertainties that accompany the clinical genome era. We propose to establish a robust framework for generation, interpretation, and clinical implementation of cancer whole exome sequencing. To accomplish this, we have assembled world-class investigators from three of the world's top institutes for oncology and genomics: the Dana-Farber Cancer Institute (DFCI), the Broad Institute, and the Brigham and Women's Hospital (BWH). This team will leverage a major institutional partnership in personalized cancer medicine already in place at DFCI and BWH. After consent, patients will be enrolled into a clinical study (Project 1) wherein tumor and normal genomic DNA are procured and transferred to the Broad Institute for whole exome sequencing, analysis, and interpretation (Project 2). The resulting list of actionable alterations will be provided to the BWH diagnostic CLIA lab for validation and returned to the Project 1 clinical team to inform the care of cancer patients. The CLIA lab will independently query known actionable mutations using orthogonal approaches. In parallel, we will conduct longitudinal surveys and qualitative interviews of patients and their oncologists at various points surrounding the informed consent, data delivery and decision-making processes (Project 3). Upon completion, we will have configured a clinical formalism through which oncologists incorporate genomic information into their management plan and report the results to cancer patients and their families. The overall initiative will be jointly led by Drs. Levi Garraway and Pasi Janne. D. Garraway (Project 2 PI) is a cancer genome scientist and medical oncologist who has made pioneering advances at the interface of cancer genome characterization, targeted therapeutics, and personalized cancer medicine. Dr. Janne (Project 1 PI) is a translational oncologist who has made major discoveries highlighting the role of genomics in response and resistance to targeted anticancer agents. Dr. Steven Joffe (Project 3 PI) has made seminal contributions pertaining to the ethics of research, and Dr. Stacy Gray (Project 3 co-PI) is an outstanding'junior investigator focusing on communication/policy issues surrounding the return of genetic tests to cancer patients. The overall investigative team consists of world leaders in translational oncology, cancer genomics, clinical cancer genetics, computational biology, outcomes research, and research ethics. Together, these efforts will define a scalable model for the integration of clinical sequencing into cancer care.